This project identifies core psychological and behavioral processes and their underlying neural mechanisms related to anxiety and anxiety disorders. Using a high-spatial resolution 7 Tesla scanner, we map the functional connectivity of small structures implicated in fear and anxiety, including the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). We also characterize the effects of normal anxiety and pathological anxiety on neurocognitive and neurobehavioral processes. This work provides clues as to the boundary between normal and abnormal mechanisms, and helps identify clinical biomarkers, i.e., features that distinguish normal from abnormal anxiety. While most research focus on fear, which is an emergency flight or fight reaction to an imminent threat, our work deals with anxiety. Anxiety is a sustained state of apprehension about future and uncertain threats. Anxiety is about worries, hypervigilance, and cautious behavior, also called behavioral inhibition. We induce anxiety by threatening participants with mildly unpleasant shocks delivered on one wrist. These shocks make participants anxious, but the shocks are safe. The intensity of the shock is set by the subject themselves at the beginning of the experiment at a level that they feel uncomfortable but tolerable. Research in animals provide strong guidance to study the mechanisms underlying fear and anxiety humans. Our lab focuses more specifically on two structures, the CeA and the BNST. These structures are difficult to study in humans because of their small size. However, new powerful neuroimaging scanners now enable us to gain better insights into these brain regions. We have shown that the CeA and the BNST are connected to many of the same structures that have been identified in animals, suggesting close anatomical conservation across mammalian species (Gorka et al., 2018). However, we also found new connections with the BNST, especially in cortical regions involved in cognition, emotion regulation, and cognitive control. Thus, the BNST interacts with higher cortical regions, and may be responsible for the way we think and feel when anxious. To explore this possibility, we examined how anxiety induced experimentally changes how the CeA and the BNST communicate with the rest of the brain (Torrisi et al 2018). We found that, above all, the brain becomes more active when anxious; many cortical regions increase their communication with all other parts of the brain. The CeA also becomes more strongly connected, especially with the thalamus. The thalamus is a complex structure with many nuclei. It serves to filter sensory information, modulate arousal, and reorient attention to threat. One possibility is that the strengthening of CeAthalamus communication reflects the maintenance of salient information originating from the CeA, helping keep focus on potential threat. While anxiety increases connectivity among many brain regions, it decreases the connectivity of BNST with cortical regions, specifically the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), and with a subcortical region, the nucleus accumbens. One possible interpretation of the changes in BNST-cortical connectivity during anxiety induced by anticipation of shocks is that the brain shifts its attention from internal concerns toward monitoring the environment. This is suggested by the fact that the vmPFC and the PCC are components of the so-called default mode network, a neural circuit more particularly involved in self-referential processing and mind wandering. To make a medical diagnosis, clinicians rely on signs, which can be observed and quantified (e.g., white blood cell count), and symptoms, which are subjective information gathered via patients self-report and clinicians observation of patients. One of the main impediments to progress in anxiety research is that, unlike for many medical conditions, there is no objective sign associated with anxiety disorders. The discovery of new treatments for anxiety disorders will depend on discovering objective signs of anxiety disorders. We attempt to identify objective signs of the cognitive and behavioral symptoms of anxiety using cognitive tasks that probe basic mechanisms associated with anxiety such as hypervigilance, working memory, and behavioral inhibition. One key finding is that anxiety in control participants facilitates behavioral inhibition and cautious behavior (Grillon et al 2017). This effect can be demonstrated in go/nogo tasks in which frequent go trials (90%) are presented among infrequent nogo trials (10%). Participants must press a key when they see a O on the screen and stop their response when they see a Y. The task is more difficult than it seems. Because there are many O (go trials) and few Y (nogo trial), over time participants develop an automatic response to go trials, which is extremely difficult to stop on nogo trials. We have shown that anxiety facilitates stopping on nogo trials, perhaps because anxiety facilitates caution and the ability to stop ongoing behavior. Such ability would be adaptive: the ability to stop ongoing movement rapidly when danger looms in the environment could help prevent detection. Anxious patients are also better at stopping when anxious (Grillon et al 2017). However, this improvement in stopping ability to nogo trials is associated with increased error on go trials, i.e., anxious patients fail to response to go trial. In other words, anxious patients show excessive response inhibition. They adequately stop responding to nogo trials but also stop responding on a few go trials. This may be a part of a more generalized tendency to show behavioral inhibition, which is one of the characteristics of anxiety disorders. We are currently examining the neural circuits involved in response inhibition in go/nogo tasks in the hope that this will help us identify underlying neural deficits associated with behavioral inhibition in anxious patients. Executive functions refer to a set of mental skills that let people plan, organize, and complete tasks. Thus, executive functions play a crucial regulatory role in mental health. Executive functions are impaired in anxiety; anxious patients complain that they cannot concentrate, are easily distracted, and have trouble completing tasks. A key executive function is working memory (WM), a short-term memory system that help remember information and protect this information from distraction to guide behavior. WM provides the mental space not just to manipulate cognitive information, but also for anxious thoughts. For this reason, we examine the interaction between anxiety and WM to better understand the mechanisms responsible for the filtering distraction, mental representation of threat, and maintenance of anxious thoughts, as well as self-regulation processes. Control participants can maintain their performance on WM task during experimental anxiety because they implement executive control to filter out threat information. However, anxious patients are distracted by their anxiety, which impairs with their WM performance, probably because they cannot implement sufficient executive control (Balderston et al 2017). Consistent with this hypothesis, we have reported that anxious patients show poor engagement of the dorsolateral prefrontal cortex, a key executive control region, during such tasks (Balderston et al 2017). Taken together, we have identified several behavioral and cognitive deficits in anxious patients as we are starting to uncover the underlying neural mechanisms responsible for such deficits. Critically, this work has the potential to dramatically change our approach to classification and treatment of anxiety disorders, and hopefully to improve the life of people suffering from anxiety.